Effects of EGFR Expression on Anti-tumor Efficacy of Vandetanib or Cediranib Combined with Radiotherapy (RT) in U87 Human Glioblastoma (GBM) Xenografts

Introduction: Vandetanib is a receptor tyrosine kinase inhibitor (RTKI) with activity against vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR). Cediranib is a highly potent VEGF RTKI that inhibits all three VEGF receptors. In this study we investigated the effect of exogenous overexpression of EGFR on sensitivity of human GBM U87 xenografts to vandetanib or cediranib, alone or in combination with RT. American Association for Cancer Research (AACR) 101st Annual Meeting April 17-21, Washington, DC

Effect of Cediranib, Temozolamide and Radiotherapy in U87 GBM wtEGFR and EGFRvIII-expressing Xenografts

Introduction: Glioblastomas (GBM) frequently overexpress the epidermal growth factor receptor (wtEGFR) or its mutant, EGFRvIII contributing to radioresistance. New treatment strategies for GBM include blockade of EGFR signaling and angiogenesis. Cediranib (CD) is a highly potent VEGFR-2 RTKI that inhibits all three VEGF receptors. This study investigated the radiosensitizing potential of CD in combination with temozolamide (TMZ) in U87 GBM xenografts expressing wtEGFR or EGFRvIII. Radiation Research Society (RRS) 8th Annual Meeting September 25-29, Maui, H

Evolving Role of Vorinostat Combined with Radiation Therapy in the Treatment of Brain Tumors, from the Lab to the Clinic

Purpose/Objective(s): Radiation therapy (RT) is a critical element in the treatment of both brain metastases and glioblastoma (GBM). Temozolomide (TMZ) has an established role in the upfront treatment of GBM. Down-regulated mismatch repair (MMR) is a known mechanism of resistance to TMZ. Vorinostat (SAHA), an HDAC inhibitor, has successfully been combined with a number of cytotoxic agents, including ionizing radiation (IR). We performed a series of preclinical and clinical studies to examine the role of SAHA in the treatment of brain tumors. American Society for Therapeutic Radiation Oncology (ASTRO) 52nd Annual Meeting October 31 - November 4, San Diego, C

Functional Antagonism Between Vorinostat and Temozolomide when Combined with Ionizing Radiation (IR) in Glioblastoma

Background: Glioblastoma is the most common primary adult brain tumor. Surgery followed by radiation therapy in combination with temozolomide (Tmz) produces a median survival of 14.6 months. Tmz is a DNA akylating agent that leads to the mispairing of guanine residues with thymine. An intact mismatch-repair mechanism (MMR) converts the mispaired thymine into a lethal double-strand DNA break. Vorinostat (SAHA), an HDAC inhibitor, has been shown to act as a radiosensitizer, possibly through inhibition of DNA repair. SAHA has successfully been combined with a number of cytotoxic agents. We hypothesized that SAHA would further potentiate the radiosensitizing properties of Tmz in glioblastoma. American Association for Cancer Research (AACR) 101st Annual Meeting April 17-21, Washington, D

Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126

Current experimental and clinical knowledge supports the optimisation of endothelial cell targeting using a strategy combining anti-EGFR drugs with antivascular agents. The purpose of the present study was to examine the effects of the association of ZD6126, an antivascular microtubule-destabilising agent, with gefitinib and irradiation on the growth of six head and neck human cancer cell lines xenografted in nude mice and to study predictive and molecular factors responsible for antitumour effects. CAL33- and Hep-2-grafted cell lines were the most sensitive to ZD6126 treatment, with VEGF levels significantly higher (P=0.0336) in these tumour xenografts compared to Detroit 562- and CAL27-grafted cell lines with relatively low VEGF levels that were not sensitive to ZD6126. In contrast, neither IL8 levels nor EGFR expression was linked to the antitumour effects of ZD6126. ZD6126 in combination with gefitinib resulted in a synergistic cytotoxic interaction with greater antitumour effects than gefitinib alone. The synergistic interaction between ZD6126 and gefitinib was corroborated by a significant decrease in CD31 labelling. The present study may serve for future innovative clinical applications, as it suggests that VEGF tumour levels are possible predictors for ZD6126 antitumour efficacy. It also supports the notion of antitumour supra-additivity when combining gefitinib and ZD6126, and identifies neoangiogenesis as the main determinant of this synergistic combination

Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel

The clinical success of small-molecule vascular disrupting agents (VDAs) depends on their combination with conventional therapies. Scheduling and sequencing remain key issues in the design of VDA–chemotherapy combination treatments. This study examined the antitumour activity of ZD6126, a microtubule destabilising VDA, in combination with paclitaxel (PTX), a microtubule-stabilising cytotoxic drug, and the influence of schedule and sequence on the efficacy of the combination. Nude mice bearing MDA-MB-435 xenografts received weekly cycles of ZD6126 (200 mg kg−1 i.p.) administered at different times before or after PTX (10, 20, and 40 mg kg−1 i.v.). ZD6126 given 2 or 24 h after PTX showed no significant benefit, a result that was attributed to a protective effect of PTX against ZD6126-induced vascular damage and tumour necrosis, a hallmark of VDA activity. Paclitaxel counteracting activity was reduced by distancing drug administrations, and ZD6126 given 72 h after PTX potentiated the VDA's antitumour activity. Schedules with ZD6126 given before PTX improved therapeutic activity, which was paralleled by a VDA-induced increase in cell proliferation in the viable tumour tissue. Paclitaxel given 72 h after ZD6126 yielded the best response (50% tumours regressing). A single treatment with ZD6126 followed by weekly administration of PTX was sufficient to achieve a similar response (57% remissions). These findings show that schedule, sequence and timing are crucial in determining the antitumour efficacy of PTX in combination with ZD6126. Induction of tumour necrosis and increased proliferation in the remaining viable tumour tissue could be exploited as readouts to optimise schedules and maximise therapeutic efficacy

Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

Surgical resection followed by radiotherapy and temozolomide in newly diagnosed glioblastoma can prolong survival, but it is not curative. For patients with disease progression after frontline therapy, there is no standard of care, although further surgery, chemotherapy, and radiotherapy may be used. Antiangiogenic therapies may be appropriate for treating glioblastomas because angiogenesis is critical to tumor growth. In a large, noncomparative phase II trial, bevacizumab was evaluated alone and with irinotecan in patients with recurrent glioblastoma; combination treatment was associated with an estimated 6-month progression-free survival (PFS) rate of 50.3%, a median overall survival of 8.9 months, and a response rate of 37.8%. Single-agent bevacizumab also exceeded the predetermined threshold of activity for salvage chemotherapy (6-month PFS rate, 15%), achieving a 6-month PFS rate of 42.6% (p < 0.0001). On the basis of these results and those from another phase II trial, the US Food and Drug Administration granted accelerated approval of single-agent bevacizumab for the treatment of glioblastoma that has progressed following prior therapy. Potential antiangiogenic agents-such as cilengitide and XL184-also show evidence of single-agent activity in recurrent glioblastoma. Moreover, the use of antiangiogenic agents with radiation at disease progression may improve the therapeutic ratio of single-modality approaches. Overall, these agents appear to be well tolerated, with adverse event profiles similar to those reported in studies of other solid tumors. Further research is needed to determine the role of antiangiogenic therapy in frontline treatment and to identify the optimal schedule and partnering agents for use in combination therapy

Acute tumor response to ZD6126 assessed by intrinsic susceptibility magnetic resonance imaging

AbstractThe effective magnetic resonance imaging (MRI) transverse relaxation rate R2* was investigated as an early acute marker of the response of rat GH3 prolactinomas to the vascular-targeting agent, ZD6126. Multigradient echo (MGRE) MRI was used to quantify R2*, which is sensitive to tissue deoxyhemoglobin levels. Tumor R2* was measured prior to, and either immediately for up to 35 minutes, or 24 hours following administration of 50 mg/kg ZD6126. Following MRI, tumor perfusion was assessed by Hoechst 33342 uptake. Tumor R2* significantly increased to 116 ± 4% of baseline 35 minutes after challenge, consistent with an ischemic insult induced by vascular collapse. A strong positive correlation between baseline R2* and the subsequent increase in R2* measured 35 minutes after treatment was obtained, suggesting that the baseline R2* is prognostic for the subsequent tumor response to ZD6126. In contrast, a significant decrease in tumor R2* was found 24 hours after administration of ZD6126. Both the 35-minute and 24-hour R2* responses to ZD6126 were associated with a decrease in Hoechst 33342 uptake. Interpretation of the R2* response is complex, yet changes in tumor R2* may provide a convenient and early MRI biomarker for detecting the antitumor activity of vascular-targeting agents